The present invention relates to a selective production method of a mixed acid anhydride and a production method of an amide compound, which methods are useful in the production of pharmaceuticals and intermediates thereof.
A mixed acid anhydride of a carboxylic acid derivative has been known as an intermediate for producing an amide compound. Said anhydride has been typically produced, for example, in a small scale production by quickly adding a carboxylic add activating agent to a mixed solution of a carboxylic acid such as an amino acid having a protected amino group and an organic base, and immediately thereafter, within a few minutes, reacted with amines to produce amides due to its instability to a longer reaction time (J. Amer. Chem. Soc., 89, 5012 (1967), and Org. Reaction, 12, 157 (1962)).
According to the present invention, a mixed acid anhydride can be selectively produced, and an amide compound can be produced in a good chemical or optical yield not only in a laboratory scale but also in an industrial scale of production where a longer reaction time is required.
The present invention provides
a method for producing a mixed acid anhydride of formula (1):
R1C(O)OY(O)n(R2)pxe2x80x83xe2x80x83(1)
wherein R1, R2, Y, n and p denote the same as defined below, which comprises adding
a carboxylic acid of formula (2);
R1COOHxe2x80x83xe2x80x83(2)
xe2x80x83wherein R1 denotes
a hydrogen atom,
an optionally substituted saturated or unsaturated hydrocarbyl group, or
an optionally substituted hetero ring, and
an organic base to a solution of a carboxylic acid activating agent of formula (3);
(R2)pY(O)nXxe2x80x83xe2x80x83(3)
xe2x80x83wherein R2 denotes
an optionally substituted alkyl group (e.g., C1-C6 chain, branched or cyclic alkyl group, which may be substituted with a halogen atom),
an optionally substituted aryl group (e.g., a phenyl which may be substituted with a halogen or C1-C3 alkyl group),
an optionally substituted chain or cyclic alkoxy group (e.g., C1-C6 chain or cyclic alkoxy group), or
an optionally substituted aryloxy group (e.g., a phenoxy group which may be substituted with a halogen or C1-C3 alkyl group),
Y denotes
a carbon atom, a phosphorus atom, or a sulfur atom,
X denotes
a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group or a group of formula:
xe2x80x83(R2)pY(O)nOxe2x80x94,
xe2x80x83wherein
R2 is the same as defined above,
n and p are an integer of 1 or 2; and
when Y is a carbon atom, n=1 and p=1,
when Y is a phosphorous atom, n=1 and p=2, and
when Y is sulfur atom, n=2 and p=1 and R2 denotes an optionally substituted alkyl or aryl group; and
a method for producing an amide compound of formula (4); 
xe2x80x83wherein
R1 denotes the same group as described above,
R3 and R4 independently denote
a hydrogen atom,
an optionally substituted saturated or unsaturated hydrocarbyl group,
an optionally substituted hetero ring,
a protective group for an amino group, or
R3 represents a group of formula: xe2x80x94OR30, or xe2x80x94NR30R31, wherein
R30 represents an optionally substituted alkyl group, or an optionally substituted aryl group and R31 represents a hydrogen atom or an optionally substituted aryl group, and
R3 and R4 may be bonded to form a ring, which comprises
reacting the mixed acid anhydride of formula (3) obtained as above, with an amine of formula (5);
NHR3R4xe2x80x83xe2x80x83(5)
xe2x80x83wherein R3 and R4 independently denote the same group as described above.
Hereinafter, the present invention will be described in detail.
First a description will be made to R1.
In the optionally substituted saturated or unsaturated hydrocarbyl group represented by R1 and other groups, the saturated or unsaturated hydrocarbyl group means, unless otherwise specified hereinafter,
a straight, branched or cyclic alkyl group (e.g., C1-C18 alkyl group),
an alkenyl or cycloalkenyl group (e.g., C2-C5 alkenyl or C5-C6 cycloalkenyl),
an alkynyl group (e.g., C3-C4 alkynyl),
an aryl group, which includes a phenyl, tolyl, biphenyl and naphthyl group,
an aralkyl, arylalkenyl or arylalkynyl group, which respectively means a phenyl-, biphenyl- or naphthyl-substituted alkyl (e.g, C1-C4 alkyl such as methyl, ethyl, propyl, butyl), alkenyl (e.g., C2-C4 alkenyl such as vinyl, propenyl, methally), or alkynyl (e.g, C3-C4 alkylnyl such as propynyl, butynyl) group.
The hetero ring means a pyridyl group, a 1,3-oxazole group, a 1,3-thiazole group, a furyl group, a tetrahydrofuryl group, a thienyl group, an imidazole or alkyleneimine group (e.g., C2-C11) of which nitrogen atoms are protected by a protecting group, or the like hereinafter.
The straight, branched or cyclic alkyl group, the alkenyl or cycloalkenyl group, the alkynyl group, the aryl group, the aralkyl, arylalkenyl or arylalkynyl group and the hetero ring may be each substituted with
(a) a hydroxy group or a halogen atom, or
(b) an amino group of formula: R11R12Nxe2x80x94 and optionally further with
at least one group selected from
a carbamoyl group, a methylmercapto group,
a 4-pyrimidinone-3-yl group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
a mercapto, guanidyl, carboxyl, hydroxy or imidazolyl group, wherein R11 represents a hydrogen atom or an amino-protecting group, R12 represents an amino-protecting group, or a group of formula: R13xe2x80x94CO,
wherein R13 represents a saturated or unsaturated hydrocarbyl group or a hetero ring, as defined above, which may be substituted with
(c) a hydroxy group, or a halogen atom, or
(d) a group of formula: R14R15Nxe2x80x94 and optionally further with at least one group selected from
a carbamoyl group, a methylmercapto group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
an amino, mercapto, guanidyl, carboxyl, hydroxy, imidazolyl group, wherein R14 is an amino-protecting group, and R15 represents a hydrogen atom, a saturated or unsaturated hydrocarbyl group, a hetero ring or an amino-protecting group,
provided that said amino, mercapto, guanidyl, carboxyl, hydroxy and imidazolyl groups which may present in R1, R2, R3 and substituent groups contained therein are in a protected form.
First preferred group for R1 is an alkyl (e.g, C1-C5) group substituted with
(b) an amino group of formula: R11R12Nxe2x80x94 and optionally further with
at least one group selected from
a carbamoyl group, a methylmercapto group,
a 4-pyrimidinone-3-yl group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
a mercapto, guanidyl, carboxyl, hydroxy or imidazolyl group, wherein R11 represents a hydrogen atom or an amino-protecting group, R12 represents an amino-protecting group, or a group of formula: R13xe2x80x94CO,
wherein R13 represents a saturated or unsaturated hydrocarbyl group or the hetero ring, as defined above, which may be substituted with
(c) a hydroxy group, or a halogen atom, or
(d) a group of formula: R14R15Nxe2x80x94 and optionally further with at least one group selected from
a carbamoyl group, a methylmercapto group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
an amino, mercapto, guanidyl, carboxyl, hydroxy, imidazolyl group, wherein R14 is an amino-protecting group, and R15 represents a hydrogen atom or an amino-protecting group,
provided that said amino, mercapto, guanidyl, carboxyl, hydroxy and imidazolyl groups are in a protected form.
Specific examples of the optionally substituted (C1-C18) alkyl group include a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group, a n-undecyl group, an n-dodecyl group, a n-tridecyl group, a n-tetradecyl group, a n-pentadecyl group, an n-hexadecyl group, an n-heptadecyl group, an octadecyl group, an isopropyl group, an isobutyl group, a 3-methylbutyl group, a 4-methylpentyl group, a 5-methylhexyl group, a 6-methylheptyl group, a 7-methyloctyl group, a 8-methylnonyl group, a see-butyl group, a 2-methylbutyl group, a 2-methylpentyl group, a 2-methylhexyl group, a 2-methylheptyl group, a 2-methyloctyl group, a 2-methylnonyl group, a t-butyl group, a cyclohexyl group, a 1-hydroxy-n-butyl group, a 2-hydroxy-1-cyclohexyl group, and the like, wherein the hydroxy groups are in a protected form.
Specific examples of the optionally substituted aryl or aralkyl group include an xcex1-phenethyl group, a 1-hydroxy-1-phenylmethyl group, or the like, a phenyl group, a 4-methylphenyl group,
a 4-phenylphenyl group, a 4-hydroxyphenyl group, or the like, wherein the hydroxy groups are in a protected form.
In addition, R1 group includes the following sub-group of formula:
R11R12Nxe2x80x94Axe2x80x94xe2x80x83xe2x80x83(6)
wherein R11 and R12 are the same as defined above, and xe2x80x9cAxe2x80x9d represents
alkylene groups such as an ethylene group, a cyclohexylene group or the like,
alkenylene groups such as propenylene, cyclohexenylene or the like,
alkynylene groups such as propynylene or the like,
arylene groups such as a phenylene group or the like,
an aralkylene groups such as phenylmethylene group or the like,
arylalkenylene groups such as phenylpropynylene or the like,
arylalkynylene group such as phenypropenylene or the like, and
hetero rings such as an oxazole ring, a thiazole ring, an imidazole ring or the like.
Specific examples of the amino acids, which contain the structure of formula (6) include
3-aminopropionic acid, 3-aminobutyric acid, 3-amino-3-phenylbutyric acid, 4-aminobutyric acid, 3-aminovaleric acid, 4-aminovaleric acid, 5-aminovaleric acid, piperidine-3-carboxylic acid, piperidine-4-carboxylic acid, 2-aminocyclohexanecarboxylic acid, 3-aminocyclohexanecarboxylic acid, 4-aminocyclohexanecarboxylic acid, 3-aminoacrylic acid, 3-aminomethacrylic acid, 3-aminocyclohexene-1-carboxylic acid, 4-aminocyclohexene-1-carboxlic acid, o-aminobenzoic acid, m-aminobenzoic acid, p-aminobenzoic acid, o-aminophenylacetic acid, m-aminophenylacetic acid, p-aminophenylacetic acid, o-aminocinnamic acid, m-aminocinnamic acid, p-aminocinnamic acid, 3-(2-aminophenyl)-2-propionic acid, 3-(3-aminophenyl)-2-propionic acid, 3-(4-aminophenyl)-2-propionic acid, 2-amino-4-oxazolecarboxylic acid, 2-amino-4-thiazolecarboxylic acid, 2-amino-4-diazolecarboxylic acid or the like.
The acid derivatives represented by formula (2) include following xcex1-amino acid derivatives of formula (7); 
wherein R5 and R6 represent a hydrogen atom or a saturated or unsaturated hydrocarbyl group or a hetero ring, both of which may be each substituted with
(a) a hydroxy group or a halogen atom, or
(b) at least one group selected from
a carbamoyl group, a methylmercapto group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with a protected amino and carboxyl groups, and
a protected amino, mercapto, guanidyl, carboxyl, hydroxy or imidazolyl group,
R11 is a hydrogen atom or an amino-protecting group,
R12 represents an amino-protecting group or a group of formula: R13COxe2x80x94, wherein R13 represents a saturated or unsaturated hydrocarbyl group or the hetero ring, which may be substituted with
(c) a hydroxy or a halogen atom, or
(d) a group of formula: R14R15Nxe2x80x94 and optionally further with at least one group selected from
a carbamoyl group, a methylmercapto group,
alkyl(C1-C3)dithio group, of which alkyl is substituted with a protected amino and carboxyl groups,
an amino, mercapto, guanidyl, carboxyl, hydroxy, or imidazolyl group, wherein R14 is an amino-protecting group, R15 represents a hydrogen atom or an amino-protecting group, and
R11 and R12, and R14 and R15 may independently form an alkyleneimie group such as aziridine, azetidine, or a 4-pyrimidinone-3-yl group or the like,
provided that said amino, mercapto, guanidyl, carboxyl, hydroxy and imidazolyl group are in a protected form.
Specific examples of the xcex1-amino acids, which are encompassed by the formula (7) include
alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, histidine, hydroxylysine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, valine, 1-naphthylalanine, 2-naphthylalanine, pipecoline, ornithine, 2,2-dimethylglycine, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 4-pyrimidinone-3-acetic acid or the like, of which functional groups other than carboxyl groups are protected.
Examples of the alkyleneimine compounds, which is encompassed by the formula (7) above, include a cyclic xcex1-amino acid derivative of formula (8): 
wherein R12 and R6 independently denote the same as described above, and m denotes an integer from 1 to 10.
Specific examples of the compounds defined by the general formula (8) include
aziridinecarboxlic acid, azetidinecarboxyic acid, proline, hydroxyproline, pipecolic acid, 2-carboxyhexamethyleneimine, 2-carboxyheptamethyleneimine, 2-carboxyoctamethyleneimine, 2-carboxynonamethyleneimine, 2-carboxydecamethyleneinmine, 2-carboxyundecamethyleneimine, 2-carboxydodecamethyleneimine, 2-carboxytridecamethyleneimine, 2-carboxytetradecamethyleneimine, 2-carboxypentadecamethyleneimine, 2-carboxyhexadecamethyleneimine, 2-carboxyheptadecamethyleneimine, 2-carboxyoctadecamethyleneimine, 2-carboxynonadecamethyleneimine, 2-carboxyeicosamethyleneimine, 2-carboxyheneicosamethyleneimine or the like, of which nitrogen atom is protected.
Specific examples of the dipeptide, which is encompassed by the formula (7) and can be derived from the specified xcex1-amino acids above include
alanyl-azetidinecarboxylic acid, alginyl-azetidinecarboxylic acid, asparaginyl-azetidinecarboxylic acid, aspartyl-azetidinecarboxylic acid, cysteinyl-azetidinecarboxylic acid, cystyl-azetidinecarboxylic acid, glutamyl-azetidinecarboxylic acid, glycyl-azetidinecarboxylic acid, histidyl-azetidinecarboxylic acid, hydroxylysyl-azetidinecarboxylic acid, isoleucyl-azetidinecarboxylic acid, leucyl-azetidinecarboxylic acid, lysyl-azetidinecarboxylic acid, methionyl-azetidinecarboxylic acid, phenylalanyl-azetidinecarboxylic acid, prolyl-azetidinecarboxylic acid, seryl-azetidinecarboxylic acid, threonyl-azetidinecarboxylic acid, tryptophyl-azetidinecarboxylic acid, tyrosyl-azetidinecarboxylic acid, valyl-azetidinecarboxylic acid, naphthylalanyl-azetidinecarboxylic acid, pipecolyl-azetidinecarboxylic acid, ornithyl-azetidinecarboxylic acid, 2,2-dimethylglycyl-azetidinecarboxylic acid, 4-pyrimidinon-3-acetyl-azetidinecarboxylic acid, azetidyl-azetidinecarboxylic acid or the like, of which functional groups other than xcex1-carboxyl group are protected.
Specific examples of the protecting groups in the present specification, for example, those represented by R11, R12, R13, R14 and R15 which protect the functional groups such as a hydroxy, mercapto, amino, carboxyl, or guanidyl group in R1, include carbamate type protective groups such as
a methyloxycarbonyl group, an ethyloxycarbonyl group, an isobutyloxycarbonyl group, a t-butyloxycarbonyl group, a t-amyloxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group, a 2-trimethylsilylethyloxycarbonyl group, a phenylethyloxycarbonyl group, a 1-(1-adamantyl)-1-methylethyloxycarbonyl group, a 1,1-dimethyl-2-haloethyloxycarbonyl group, a 1,1-dimethyl-2,2-dibromoethyloxycarbonyl group, a 1,1-dimethyl-2,2,2-trichloroethyloxycarbonyl group, a methyl-1-(4-biphenylylethyloxycarbonyl group, a 1-(3,5-di-tert-butylphenyl)-1-methylethyloxycarbonyl group, a 2-(2xe2x80x2-pyridyl)ethyloxycarbonyl group, a 2-(4xe2x80x2-pyridyl)ethyloxycarbonyl group, a 2-(N,N-dicyclohexylcarboxamido)ethyloxycarbonyl group, a 1-adamantyloxycarbonyl group, a vinyloxycarbonyl group, an allyloxycarbonyl group, a 1-isopropylallyloxycarbonyl group, a cinnamyloxycarbonyl group, a 4-nitrocinnamyloxycarbonyl group, an 8-quinolyloxycarbonyl group, an N-hydroxypiperidinylcarbonyl group, an alkyldithiocarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-bromobenzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a 2,4-dichlorobenzyloxycarbonyl group, a 4-methylsulfinylbenzyloxycarbonyl group, a 9-anthrylmethyloxycarbonyl group, a dipheylmethyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a 9-(2,7-dibromo)fluorenylmethyloxycarbonyl group, a 2,7-di-t-butyl[9-(10,10-dioxo-thioxantyl)methyloxycarbonyl group, a 4-methoxyphenacyloxycarbonyl group, a 2-methylthioethyloxycarbonyl group, a 2-methylsulfonylethyloxycarbonyl group, a 2-(p-toluenesulfonyl)ethyloxycarbonyl group, a [2-(1,3-dithianyl)]methyloxycarbonyl group, a 4-methylthiophenyloxycarbonyl group, a 2,4-dimethylthiophenyloxycarbonyl group, a 2-phosphonioethyloxycarbonyl group, a 2-triphenylphosphonioisopropyloxycarbonyl group, a 1,1-dimethyl-2-cyanoethyloxycarbonyl group, a m-chloro-p-acyloxybenzyloxycarbonyl group, a p-(dihydroxyboryl)benzyloxycarbonyl group, a 5-benzoisooxazolylmethyloxycarbonyl group, a 2-(trifluoromethyl)-6-chromonylmethyloxycarbonyl group, a phenyloxycarbonyl group, m-nitrophenyloxycarbonyl group, a 3,5-dimethoxybenzyloxycarbonyl group, a o-nitrobenzyloxycarbonyl group, a 3,4-dimethoxy-6-nitrobenzyloxycarbonyl group, a phenyl(o-nitrophenyl)methyloxycarbonyl group or the like,
amide type protective groups such as a formyl group, an acetyl group, a chloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, a phenylacetyl group, a benzoyl group or the like, an alkyl type protective group such as benzyl group, N-di(4-methoxyphenyl)methyl group, a N-5-dibenzosuberyl group, a N-triphenylmethyl group, a (4-methoxyphenyl)diphenylmethyl group, a N-9-phenylfluorenyl group, an allyl group, a N-[2-(trimethylsilyl)ethoxy]methyl group, a N-3-acetoxypropyl group or the like.
Said xcex1-amino acids are commercially available or can be produced by a known methods and the protective groups can be optionally introduced and deprotected as discussed in detail by T. Greene in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981.
The protecting group of an amino group includes, for example, Z, Boc, tertiary-amyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Cl-Z, Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, or Fmoc. The carboxy-protecting group that can be used includes but is not limited to the above-mentioned as well as 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, benzyloxycarbonylhydrazido, tertiary-butoxycarbonylhydrazido, tritylhydrazido and the like. Preferred is Boc.
The hydroxy group of serine and threonine can be protected by esterification or etherification. The group suited for said esterification includes carbon-derived groups such as lower alkanoyl groups, e.g. acetyl etc., aroyl groups, e.g. benzoyl etc., benzyloxycarbonyl, and ethoxycarbonyl. The group suited for said etherification includes benzyl, tetrahydropyranyl, and tertiary-butyl.
The protective group for the phenolic hydroxyl group of tyrosine includes 2-nitrobenzyl, Brxe2x80x94Z, tertiary-butyl or the like.
The protecting group of imidazole for histidine or guanidyl group for arginin includes Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, DNP, benzyloxymethyl, Bum, Boc, Trt, and Fmoc.
The method for elimination of protective groups includes catalytic reduction using hydrogen gas in the presence of a catalyst such as palladium black or palladium-on-carbon, acid treatment with anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture of such acids, base treatment with diisopropylethylamine, triethylamine, piperidine, piperazine, reduction with sodium metal in liquid ammonia. The elimination reaction by the above-mentioned acid treatment is generally carried out at a temperature of 20xc2x0 C. to 40xc2x0 C. and can be conducted advantageously with addition of a cation acceptor such as anisole, phenol, thioanisole, m-cresol, p-cresol, dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedithiol. The 2,4-dinitrophenyl group used for protecting the imidazole group of histidine can be eliminated by treatment with thiophenol, while the formyl group used for protecting the indole group of tryptophan can be eliminated by alkali treatment with dilute sodium hydroxide solution or dilute aqueous ammonia as well as the above-mentioned acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol.
For example, removal of BOC protecting groups can be carried out using a strong acid such as trifluoroacetic acid or hydrochloric acid with or without the presence of a co-solvent such as dichloromethane or methanol at a temperature of about xe2x88x9230xc2x0 C. to 70xc2x0 C., preferably about xe2x88x925xc2x0 C. to about 35xc2x0 C.
The method for protecting functional groups which should not take part in the reaction of the starting material, the protective groups that can be used, the method of removing the protective groups, and the method of activating the functional groups that are to take part in the reaction can all be selected from among the known groups and methods.
A description will be made to R2 as below.
Examples of the C1-C6 chain, branched or cyclic alkyl group, which may be substituted with a halogen atom include methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, isoamyl, cyclopentyl, cyclohexyl, 3-pentyl, 2,2-dimethylpropyl, trifluoromethyl or the like
Examples of the phenyl which may be substituted with a halogen or C1-C3 alkyl group include phenyl, tolyl, mesityl, p-chlorophenyl and the like.
Examples of the C1-C6 chain or cyclic alkoxy group include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, isobutoxy, isoamyloxy, cyclopentyloxy, cyclohexyloxy, 3-pentyloxy, 2,2-dimethylpropyloxy, and the like.
Examples of the phenoxy group which may be substituted with a halogen or C1-C3 alkyl group include a phenoxy, tolyloxy, mesityloxy and the like.
Examples of the carboxylic acid activating agent defined by the formula (3) for producing a mixed acid anhydride from a carboxylic acid and a carboxylic acid activating agent in the presence of an organic base include
carbon-type acid chlorides such as methyl chlorocarbonate, ethyl chlorocarbonate, n-propyl chlorocarbonate, n-butyl chlorocarbonate, isopropyl chlorocarbonate, sec-butyl chlorocarbonate, isobutyl chlorocarbonate, isoamyl chlorocarbonate, cyclopentyl chlorocarbonate, cyclohexyl chlorocarbonate, valeryl chloride, isovaleryl chloride, diethylacethyl chloride, pivaloyl chloride or the like,
phosphorus-containing acid chlorides such as diethylphosphoryl chloride, diphenylphosphoryl chloride, diphenylphosphine chloride or the like,
sulfur-containing acid chlorides such as methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, mesitylenesulfonyl chloride or the like,
carbon-containing type acid anhydrides such as acetic acid anhydride, trifluoroacetic acid anhydride or the like,
phosphorus-containing type acid anhydrides such as, ethylmethylphosphinic acid anhydride, a cyclic trimer of n-propylphosphonic acid anhydride or the like, and
sulfur-containing type acid anhydrides such as trifluoromethanesulfonic acid anhydride. Further, bromides, fluorides, and iodides are also included in place of the chlorides.
The amount of the carboxylic acid activating agent is usually 0.5 to 5 moles, preferably 0.9 to 1.1 moles, more preferably 0.95 to 1.05 mol per mol of the carboxylic acid defined by the formula (1).
In the production of the mixed acid anhydride, examples of the organic base to be used include organic tertiary base such as trimethylamine, ethyldimethylamine, dimethyl-n-propylamine, dimethylisopropylamine, cyclohexyldimethylamine, benzyldimethylamine, dimethylphenylamine, diethylmethylamine, methyl-di-n-propylamine, methyldiisopropylamine, triethylamine, ethyldiisopropylamine, tri-n-propylamine, tri-n-butylamine, tri-n-pentylamine, tri-n-hexylamine, tri-n-heptylamine, tri-n-octylamine, quinuclidine, N-methylmorpholine, N-ethylmorpholine, N,Nxe2x80x2-dimethylpiperazine, N-methylpyrrolidine, N-methylpiperidine. pyridine, quinoline, isoquinoline, N-methylimidazole or the like. Preferred is N-methylmorpholine.
The amount of the organic base to be used is usually 0.5 to 50 moles, preferably 0.9 to 2 moles, more preferably 0.95 to 1.05 moles per mol of the carboxylic acid defined by the formula (1).
In the present invention, the carboxylic acid defined by the formula (1) may be added as a solution containing the organic base to the carboxylic acid activating agent, alternatively, the carboxylic acid solution and the organic base may be added separately and simultaneously.
Examples of a reaction solvent that can be usually used for producing the mixed acid anhydride include
esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, n-pentyl acetate, isopentyl acetate, sec-pentyl acetate, n-hexyl acetate, isohexyl acetate, sec-hexyl acetate, methyl cellosolve acetate, ethyl propionate, ethyl n-valerate or the like,
ethers such as tetrahydrofuran, dioxane, 1,3-dioxolan, dimethoxymethane, dimethoxyethane, diethyl ether, tert-butyl methyl ether or the like,
aprotic polar solvents such as acetonitrile, N,Nxe2x80x2-dimethylformamide, N,Nxe2x80x2-dimethylacetamide, N-methylpyrrolidone, pyridine or the like,
halogenated hydrocarbons such as chlorobenzene, dichloromethane, chloroform, 1,2-dichloroethane or the like, and
hydrocarbons such as toluene, xylene, benzene, hexane, heptane or the like.
The reaction temperature for producing the mixed acid anhydride is usually within a range of about xe2x88x9278 to about 30xc2x0 C. and preferably about xe2x88x9220 to about 10xc2x0 C., The mixed acid anhydride thus produced may be maintained at the reaction temperature for 30 minutes and then reacted with an amine.
In the amine compound of formula (4), the saturated or unsaturated hydrocarbyl group in the optionally substituted saturated or unsaturated hydrocarbyl group represented by R3 or R4 include
a straight, branched or cyclic alkyl group (e.g., C1-C18 alkyl group),
an alkenyl or cycloalkenyl group (e.g., C2-C5 alkenyl or C5-C6 cycloalkenyl),
an alkynyl group (e.g., C3-C4 alkynyl),
an aryl group, which include a phenyl, tolyl, biphenyl and naphthyl group,
an aralkyl, arylalkenyl or arylalkynyl group, which respectively means a phenyl-, biphenyl- or naphthyl-substituted alkyl (e.g, C1-C4 alkyl such as methyl, ethyl, propyl, butyl), alkenyl (e.g., C2-C4 alkenyl such as vinyl, propenyl, methally), or alkynyl (e.g, C3-C4 alkylnyl such as propynyl, butynyl) group.
The hetero ring means a pyridyl group, a 1,3-oxazole group, a 1,3-thiazole group, a furyl group, a tetrahydrofuryl group, a thienyl group, an imidazole or an alkyleneimine group (e.g., C2-C11) of which nitrogen atoms are protected by a protecting group, or the like.
Said saturated or unsaturated hydrocarbyl group and the hetero ring may be substituted with at least one group selected from
a halogen, nitro, alkoxy(e.g., C1-C3 alkoxy), alkyl (e.g, C-C3 alkyl), a hydroxy group, a cyano group, or a (2-alkoxyiminoacetate)-2-yl group,
a carbamoyl group, a methylmercapto group,
an alkyl(C1-C3)dithio group, of which alkyl is substituted with a protected amino and carboxyl groups,
an amino, mercapto, guanidyl, carboxyl, hydroxy, or imidazolyl group,
a group of formula: C(O)xe2x80x94R8,
wherein R8 is an alkoxy group or a group of formula: NHR80 wherein R8 and R80 represent a saturated or unsaturated hydrocarbyl group or the hetero ring, as defined above, both of which may be substituted with
a group of formula: C(O)R81 or a hydroxy group and optionally further with at least one group selected from
a carbamoyl group, a methylmercapto group,
alkyl(C1-C3)dithio group, of which alkyl is substituted with an amino and carboxyl groups,
an amino, mercapto, guanidyl, carboxyl, hydroxy, or imidazolyl group,
wherein R81 is an alkoxy group or a group of formula: NHR82 wherein R81 and R82 represent a saturated or unsaturated hydrocarbyl group or the hetero ring as defined above,
provided that said amino, mercapto, guanidyl, carboxyl, hydroxy, and imidazolyl groups above are in a protected form.
Specific examples of R30 an R31 include a methyl, an ethyl group, or a phenyl group.
Specific examples of the amines to be used include
ammonia,
a mono- or di-alkyl(C1-C12)amine such as methylamine, ethylamine, n-propylamine, n-butylamine, n-pentylamine, n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine, n-decylamine, n-undecylamine, n-dodecylamine, isobutylamine, isopentylamine, isohexylamine, isoheptylamine, isooetylamine, isononylamine, isodecylamine, isoundecylamine, isododecylamine, isopropylamine, sec-butylamine, sec-pentylamine, sec-hexylamine, sec-heptylamine, sec-octylamine, sec-nonylamine, sec-decylamine, sec-undecylamine, sec-dodecylamine, tert-butylamine, tert-pentylamine, tert-hexylamine, tert-heptylamine, tert-octylamine, tert-nonylamine, tert-decylamine, tert-undecylamine, tert-dodecylamine, dimethylamine, diethylamine, di-n-propylamine, din-butylamine, di-n-pentylamine, di-n-hexylamine, di-n-heptylamine, di-n-octylamine, di-n-nonylamine, di-n-decylamine, di-n-undecylamine, di-n-dodecylamine or the like,
an arylalkylamine, of which aralkyl group (e.g., benzyl group, or phenethyl) may be substituted with a cyano, halogen, alkoxy, alkyl) such as benzylamine, o-cyanobenzylamine, m-cyanobenzylamine, o-halobenzylamine, m-halobenzylamine, p-halobenzylamine, o-methoxybenzylamine, m-methoxybenzylamine, p-methoxybenzylamine, o-nitrobenzylamine, m-nitrobenzylamine, p-nitrobenzylamine, o-alkylbenzylamine, m-alkylbenzylamine, p-alkylbenzylamine, phenetylamine, N-alkylbenzylamine or the like,
an arylamine, of which aryl group (e.g., phenyl or naphthyl) may be substituted with a cyano group, halogen atom (fluorine, chlorine, bromine, or idodine), nitro, alkyl, alkoxy, or aryl), such as phenylamine, o-cyanophenylamine, m-cyanophenylamine, p-cyanophenylamine, o-halophenylamine, m-halophenylamine, p-halophenylamine, o-methoxyphenylamine, m-methoxyphenylamine, p-methoxyphenylamine, o-nitrophenylamine, m-nitrophenylamine, p-nitrophenylamine, o-alkylphenylamine, m-alkylphenylamine, p-alkylphenylamine, N-alkylphenylamine, N-arylphenylanine or the like,
amino acid esters such as azetidine carboxylic acid ester, alanine ester, arginine ester, asparagine ester, aspartic acid ester, cysteine ester, cystine ester, glutamic acid ester, glutamine ester, glycine ester, histidine ester, hydroxylysine ester, hydroxyproline ester, isoleucine ester, leucine ester, lysine ester, methionine ester, phenylalanine ester, proline ester, serine ester, threonine ester, tryptophane ester, tyrosine ester, valine ester, naphthylalanine ester, pipecolic acid ester, ornithine ester, or the like,
peptides such as alanyl-azetidinecarboxylate, arginyl-azetidinecarboxylate, asparaginyl-azetidinecarboxylate, aspartyl-azetidinecarboxylate, cysteinyl-azetidinecarboxylate, cystyl-azetidinecarboxylate, glutamyl-azetidinecarboxylate, glycyl-azetidinecarboxylate, histidyl-azetidinecarboxylate, hydroxylysyl-azetidinecarboxylate, isoleucyl-azetidinecarboxylate, leucyl-azetidinecarboxylate, lysyl-azetidinecarboxylate, methionyl-azetidinecarboxylate, phenylalanyl-azetidinecarboxylate, proryl-azetidinecarboxylate, seryl-azetidinecarboxylate, threonyl-azetidinecarboxylate, tryptophyl-azetidinecarboxylate, tyrosyl-azetidinecarboxylate, valyl-azetidinecarboxylate, naphthylalanyl-azetidinecarboxylate, pipecolyl-azetidinecarboxylate, ornithyl-azetidinecarboxylate, 2,2-dimethylglycyl-azetidinecarboxylate, 4-pyrimidinon-3-acetyl-azetidinecarboxylate, azetidyl-azetidinecarboxylate or the like,
2-aminooxazoles, 2-aminoimidazoles, 2-aminothiazoles, hydroxylamines such as N,O-dimethylhydroxylamines, and hydrazines such as 1-methyl-1-phenylhyrazine.
The amines may be hydrochlorides, methanesulfonic acid salts, p-toluenesulfonic acid salts, benzenesulfonic acid salts or the like. In such cases, the base in an amount of equal to or more than the equivalent to the organic amine is used to liberate it in the reaction system.
The amount of the amine to be used is usually about 0.5 to about 5 moles, preferably 0.7 to 2 moles per mol of the carboxylic acid defined by the general formula (1).
When Y is not a carbon atom and R2 is not an optionally substituted alkoxy or aryloxy group, a base is usually used to neutralize an acid formed in the amidation reaction of the amine and the mixed acid anhydride of the present invention. The amount of the base is usually 1 mol per mol of the mixed acid anhydride, if necessary. Examples of the base include the tertiary organic amines as exemplified above.
As a reaction solvent to be used for the amidation reaction, the foregoing solvents exemplified for those to be used for the mixed acid anhydride production can be used. The amount is not specifically limited.
The reaction temperature of the amidation reaction is usually within a range of xe2x88x9278 to 50xc2x0 C. and preferably xe2x88x9220 to 30xc2x0 C.
After completion of the reaction, the obtained reaction mixture is successively washed with an aqueous acid, water, alkaline and water and an amide compound as defined by the general formula (5) can be obtained.
In the production of a mixed acid anhydride from the carboxylic acid and the carboxylic acid activating agent in the presence of an organic base, if the carboxylic acid activating agent is dropwise added to a solution containing the carboxylic acid and the organic base according to a conventional reaction method, as shown in the comparative examples, acid anhydrides are produced as by-products and the selectivity in the production of the mixed acid anhydride is rather low.
On the other hand, according to the reaction method of the present invention, that is, the carboxylic acid and the organic base are dropwise added to a solution containing the carboxylic acid activating agent, the selectivity of production of the mixed acid anhydride is significantly improved.
Thus, an amide compound can be produced in a good yield using the mixed acid anhydride produced in the present invention in a reaction with an amine.
The present invention is effective in the case where the yield is insufficient by a conventional method. Further, the present invention is particularly advantageous in terms of industrial production since a desired product can be obtained in a good yield for an amidation reaction by conventional method where the yield is decreased owing to long addition time.